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Open AcceStudy protocolA Randomized Multicentre Phase II Trial Comparing Adjuvant Therapy in Patients with Interferon Alpha-2b and 5-FU Alone or in Combination with Either External Radiation Treatment and Cisplatin (CapRI) or Radiation alone regarding Event-Free Survival – CapRI-2Angela Märten*1,2, Jan Schmidt1, Jennifer Ose1,2, Sabine Harig1,2, Ulrich Abel2,10, Marc W Münter3, Dirk Jäger2, Helmut Friess4, Julia Mayerle5, Guido Adler6, Thomas Seufferlein7, Thomas Gress8, Roland Schmid9 and Markus W Büchler1
Address: 1Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany, 2National Center for Tumor Diseases, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany, 3Department of Radiation Oncology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany, 4Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany, 5Department of Medicine A, Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Loeffler-Str. 23a, 17475 Greifswald, Germany, 6Department of Gastroenterology, University of Ulm, Robert Koch Strasse 8, 89081 Ulm, Germany, 7Department of Gastroenterology, University of Halle, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany, 8Department of Gastroenterology, University of Marburg, Baldingerstrasse, 35043 Marburg, Germany, 9Department of Gastroenterology, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany and 10Department of Medical Biometry, University of Heidelberg, Im Neuenheimer Feld 405, 69120 Heidelberg, Germany

Email: Angela Märten* - [email protected]; Jan Schmidt - [email protected]; Jennifer Ose - [email protected]; Sabine Harig - [email protected]; Ulrich Abel - [email protected]; Marc W Münter - [email protected]; Dirk Jäger - [email protected]; Helmut Friess - [email protected]; Julia Mayerle - [email protected]; Guido Adler - [email protected]; Thomas Seufferlein - [email protected]; Thomas Gress - [email protected]; Roland Schmid - [email protected]; Markus W Büchler - [email protected]

* Corresponding author

AbstractBackground: The 5-year survival of patients with resected pancreatic adenocarcinoma is stillunsatisfying. The ESPAC-1 and the CONKO 001 trial proofed that adjuvant chemotherapyimproves 5-year survival significantly from approximately 14% to 21%. In parallel, investigators fromthe Virginia Mason Clinic reported a 5-year survival rate of 55% in a phase II trial evaluating acombination of adjuvant chemotherapy, immunotherapy and external beam radiation (CapRI-scheme). Two other groups confirmed in phase II trials these results to a certain extent. However,these groups reported severe gastrointestinal toxicity (up to 93% grade 3 or 4 toxicity). In arandomized controlled phase III trial, called CapRI, 110 patients were enrolled from 2004 to 2007in Germany and Italy to check for reproducibility. Interestingly, much less gastrointestinal toxicitywas observed. However, dose-reduction due to haematological side effects had to be performedin nearly all patients. First clinical results are expected for the end of 2009.

Published: 26 May 2009

BMC Cancer 2009, 9:160 doi:10.1186/1471-2407-9-160

Received: 4 November 2008Accepted: 26 May 2009

This article is available from: http://www.biomedcentral.com/1471-2407/9/160

© 2009 Märten et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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BMC Cancer 2009, 9:160 http://www.biomedcentral.com/1471-2407/9/160

Methods/Design: CapRI-2 is an open, controlled, prospective, randomized, multicentre phase IItrial with three parallel arms. A de-escalation of the CapRI-scheme will be tested in two differentmodifications. Patients in study arm A will be treated as outpatients with the complete CapRI-scheme consisting of cisplatin, Interferon alpha-2b and external beam radiation and three cycles of5-fluorouracil continuous infusion. In study arm B the first de-escalation will be realised by omittingcisplatin. Next, patients in study arm C will additionally not receive external beam radiation. A totalof 135 patients with pathologically confirmed R0 or R1 resected pancreatic adenocarcinoma areplanned to be enrolled. Primary endpoint is the comparison of the treatment groups with respectto six-month event-free-survival. An event is defined as grade 3 or grade 4 toxicity, objectivetumour recurrence, or death.

Discussion: The aim of this clinical trial is to evaluate de-escalation of the CapRI-scheme. It ishypothesised that removal of cisplatin and radiotherapy will have no significant effect or only aminor impact on the clinical response but result in substantially lower toxicity.

Trial Registration: Current Controlled Trials ISRCTN79802092

BackgroundOnly 10–20% of patients with pancreatic cancer can beresected with curative intention at the time of diagnosis.Unfortunately, loco-regional recurrence and/or metastaticdisease develop in the majority of patients who undergopancreatic resection. Most patients typically relapsewithin 9–15 months form initial presentation and havemedian life expectancies of only 12–15 months withoutadjuvant therapy. The 5-year survival of patients withresected pancreatic adenocarcinoma is approximately14% for patients without adjuvant therapy [1]. Data fromtwo randomized clinical phase III trials showed that adju-vant chemotherapy results in significant increase of over-all survival (OS) and disease-free survival (DFS) [2,3].Therefore, adjuvant therapy with either 5-FU or gemcitab-ine is recommended according to the German S3 guide-lines for exocrine pancreas carcinoma [4].

Investigators form the Virginia Mason Clinic reported datafrom a phase II trial where in an adjuvant setting cisplatin,5-FU, interferon-α2b (INF-α2b) and external beam radia-tion were administered. They reported from 43 patientsoverall 5-year survival data of 55% [5]. The randomized,open, controlled, prospective, multi-centre phase III CapRI-trial was initiated in August 2004 to confirm the excellentresults of the CapRI-regimen [6]. The last patient wasenrolled end of 2007. First clinical results are expected for2009. ACOSOG and the group of Linehan et al. confirmedin phase II trials the results from the Virginia Mason Clinicto a certain extent [7,8]. These excellent results could beascribed to the several synergistic effects between the com-bined substances. Radio-sensitising properties of 5-FU andcisplatin are well known. The incorporation of INF-α2binto a combined modality treatment program seems tooffer a number of theoretical advantages. These include: 1)the radio-sensitization effects of INF-α2b and 5-FU [9,10];

2) enhanced 5-FU based bio-availability; 3) a synergisticinhibition of pyrimidine metabolism with 5-FU and 4) anindependent immunomodulatory effect of INF-α2b [11].Furthermore, our own data derived from the translationalprogram accompanying the CapRI trial showed especiallyimmunomodulatory and anti-angiogeneic effects of INF-α2b [12-17].

However, especially the ACOSOG group reported severegastrointestinal toxicities (93%) which led to enrolmentstop. Virginia Mason Clinic reported 70% grade 3 or 4 tox-icity and the group from the Washington-Universitystated 36% gastrointestinal toxicity. Although the finalsafety analysis is not yet performed we could give accounton less GI-toxicity in the CapRI-trial. Nevertheless, theregimen is challenging and reduction of side effects is auseful goal.

Methods/DesignTrial organisation and coordinationCapRI-2 is designed and coordinated by the Departmentof Surgery, University of Heidelberg and the NationalCenter for Tumor Diseases, Heidelberg (NCT). Heidelbergis responsible for overall trial management, regulatoryaffairs, statistical planning and analysis, trial registrationand reporting as well as quality assurance. The responsi-bility for external monitoring and pharmacovigilance iscarried forward to independent Contract Research Organ-isations (CRO). The trial will be conducted by a Germannetwork for pancreatic carcinoma (PC-Net) including theUniversity hospitals of Munich (Technische Universität),Marburg, Ulm, Greifswald, Halle and Heidelberg. Furtherstudy centres will be recruited. The trial is sponsored by aprivate person, Dr. Wild from Germany. The financialsponsor is not involved in the database management andhas no access to the randomisation code.



InvestigatorsPatients will be recruited by the centres who will committheir participation. Due to the multimodal nature of thetrial, all investigators will either be experienced oncolo-gists, gastroenterologists, radio-oncologists or surgeons.

Data Safety and Monitoring BoardAn independent Data Safety and Monitoring Board(DSMB) consisting of three experts (one expert in oncol-ogy, one in pancreatic carcinoma and one in biometry/biostatistics) will evaluate the clinical research data on anongoing basis to assure patient safety and study integrityfor the study. The board will monitor the trial data, in par-ticular the safety data, and makes recommendationsbased on the periodically reviewed data. Responsibilitiesare laid down in a DSMB Charta.

Medication supplyAll chemotherapeutic and immunotherapeutic agents willbe prepared and provided by the corresponding phar-macy. Medication will be prepared for each patient specif-ically and delivered just prior to administration to theoutpatient's department.

On-site MonitoringMonitoring on site will be performed according to goodclinical practice (GCP) guidelines. Monitoring will be doneby personal visits from clinical monitors according to theSOPs of the independent, external CRO. Monitors willreview the entries into CRFs on the basis of source docu-ments (30% source data verification). Data managementwill be performed by the same CRO. Pharmacovigilance isoutsourced to a further CRO specialized on safety issues.Both data bases will be aligned at the end of the trial.

Ethics approval and informed consentThe final protocol was approved by the ethics committeeof the University of Heidelberg; Medical School (AFmu-071/2008) at May 16th 2008. This clinical trial complieswith the Helsinki Declaration from 2004, the MedicalAssociation's professional code of conduct, the principlesof GCP guidelines and the Federal Data Protection Act.The trial will also be performed in keeping with local legaland regulatory requirements. The medical secrecy and theFederal Data Protection Art will be followed.

Written informed consent will be obtained from each patientin oral and written form before inclusion in the trial and thenature, scope and possible consequences of the trial havebeen explained by a physician in detail. The investigator willnot undertake any measures specifically required only for theclinical trial until valid consent has been obtained.

Patient selectionCapRI-2 focuses on hospitalised patients over 18 years ofage with resected pancreatic adenocarcinoma during a 24

months period and started in October 2008. Men andwomen over 18 years of age with histological proven R0or R1 resected [18] pancreatic adenocarcinoma will bescreened for participation in the clinical trial. Patients willbe contacted first-time by the (sub-) investigators eitherduring their postoperative hospital stay or after dischargeat the outpatient's department. A detailed overview ofrecruitment criteria for inclusion and exclusion is given intable 1.

Study designCapRI-2 is an open, controlled, prospective, randomized,multicentre phase II trial with three parallel study arms.Patients in study arm A receive a combination of 5-FU, cis-platin and external beam radiation including INF-α2badministration (CapRI). The first de-escalation step is instudy arm B where cisplatin is omitted (CapRI-light). Thesecond de-escalation will be tested in study arm C wherebeside cisplatin also radiotherapy is cancelled (CapRI-ultra-light). These treatments are offered to a heterogene-ous group of people under clinical circumstances, cover-ing a wide range, for both sexes and with heterogeneouscharacteristics/co-morbidities. No interim analysis isplaned for this trial.

Study objectivesPrimary objective is the comparison of the treatmentgroups with respect to six-month event-free survival. Anevent is defined as tumour recurrence, grade 3 or grade 4toxicity (according to CTCAE Version 3.0), or death(whichever occurs first). Secondary objectives are compar-ison of the treatment groups with respect to safety, OS,Recurrence-Free Survival (RFS), Quality of Life (QoL),screening for predictive markers, and accompanyingtranslational research focussing mainly on immunologi-cal parameters.

RandomisationAll patients enrolled will be identifiable throughout thestudy. The investigator will maintain a personal list ofpatient numbers and patient names to enable records tobe found at a later date. Upon inclusion each patientreceives a unique identification number. After thepatient's eligibility for randomisation has been assessedhe/she will be randomly assigned to one of the three treat-ment arms (1:1:1 randomization) and receive a uniquerandomisation number. By the randomisation number, itis possible to identify the order in which the patientsentered the randomized study period at the centre inquestion. Randomisation will be stratified by centre; itwill be done and documented centrally and send by fax.The randomisation list will be kept in safe and confiden-tial custody at the involved CRO. The method of randomi-sation (whether fixed block size or randomly determinedblock size) and the block sizes themselves will not be dis-closed to the study centres, the monitors or any other per-



son involved in the study conduct. This information willbe kept with the randomisation list.

Treatment schemeAfter implantation of a Port-A-Cath catheter patients willbe treated as follows (see figure 1): All arms: 200 mg/m2/day 5-FU by continuous intravenous infusion on days 1–38; 64–101, and 120–161; three million units IFN-α2bsubcutaneous three times weekly days 1–38 plus one injec-tion prior to treatment start given during week -1 (approx.day -6). Non-steroidal anti-inflammatory drugs and ster-oids should be avoided if possible during IFN-α2b treat-ment. Only arm A and B: Beside 5–FU and IFN-α2bpatients will be treated with external beam radiation: Thepancreatic bed will be covered with a minimum margin of2 cm. The porta hepatis, origins of the celiac axis and supe-rior mesenteric artery will be included. The fields mustinclude the entire duodenal C-loop as seen on pre-opera-tive CT scan. Total dose will be 50.4 Gy in 28 fractions over5.5 weeks (1.8 Gy/day). Simulation should be done withthe patient in the supine position with "arms up" position.A treatment planning CT is required to allow 3-D confor-mal treatment planning. Conventional 3-D treatment tech-niques as well as intensity modulated radiotherapy (IMRT)could be used for radiotherapy. At least a four field tech-nique for 3-D planning or a multi-field technique for IMRTis necessary. Furthermore a multi-leaf collimator is requiredto allow customized blocking and IMRT. Equipment:greater than or equal to 6 MeV photons should be used.Only study arm A): Cisplatin 30 mg/m2 IV over 60 minutes

on days 1, 8, 15, 22, 29, 36 (6 doses). Two to three hoursbefore and after Cisplatin dose the patients will receivehydration of at least 2 litres. Patients will be taught to drinkat least 1 litre during the day.

Evaluations, Toxicity-Based Dose Adjustment and follow-upPre-treatment evaluation for patients who are enrolledincludes a single low dose (3 Mio U) injection of INF-α2bprior to therapy. Blood will be drawn for intensive immu-nological studies. All patients must have appropriate laband radiographic studies conducted prior to study enrol-ment to meet eligibility criteria. Lab parameters will beobtained at least weekly and imaging will be performedevery three months. The patients will be asked at each visitfor any adverse event (AE) and concomitant medication.Quality of life (QoL) questionnaires (QLQ-C30 and thepancreas-specific Pan 26 questionnaire) will be handedout to the patients prior to therapy and after each cycle ofchemotherapy. Samples for translational research (blood,plasma and urine) will be collected at the indicated timepoints (prior and 24 hours after first IFN-α2b administra-tion, immediately prior to therapy start, first day of week3 and at staging visits) and either analyzed immediately orkept frozen at -80°C until further analysis. Samples willbe collected at each site and shipped on dry ice twice ayear to Heidelberg.

Decisions regarding weekly chemoradiation treatmentand chemotherapy dose-adjustment will be made using

Table 1: Eligibility Criteria

Inclusion criteria Exclusion criteria

• R0/R1 resected pancreatic ductal adenocarcinoma • Metastatic disease• Adequate lab parameters (bone marrow-, liver and kidney function; Hb >8.0 g/dl, WBC >3,000 cells/mm3, platelets >75,000 cells/mm3; ALT/AST ≤ 2 ULN; Creatinine ≤1.5 mg/dL and calculated or measured creatinine clearance (CrCl) of ≥ 60 ml/min).

• Previous chemo- or radiotherapy for pancreatic carcinoma

• Therapy starts within eight weeks after surgery • Previous radiotherapy in the corresponding region• Ability of patient to understand character and individual consequences of clinical trial

• Patients with known severe depression

• Written informed consent must be available before enrolment in the trial

• Patients with severe heart diseases (NYHA stadium three and four) or severe lung disease (COPD Grade III, Asthma bronchiale Grade IV)

• For women with childbearing potential, adequate contraception. • General condition worse than ECOG 2• Age ≥ 18 years • Pregnancy and lactation

• History of hypersensitivity to the investigational product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational product• Any contraindication met for any investigational product• Patients with mental diseases ICD-10-code F30, F31, F32.2 ff. or F33.2 ff.• Participation in other clinical trials and observation period of competing trials, respectively.• Serious uncontrolled acute infections at the time of therapy initiation or patients with known HIV infection, other immunodeficiencies or autoimmune diseases




Treatment schemeFigure 1Treatment scheme.


the guidelines below and based on haematologicalparameters monitored twice weekly during chemo-(radio)therapy. In case of grade 3/4 haematological toxic-ities chemotherapy should be held until resolution oruntil toxicity has resolved or dropped to a Grade 2 level.Radiation will be continued. IFN-α2b will be stopped incase of grade 4 haematological toxicities. The procedurefor patients with leukocytes between 1.0 and 1.5/nl willbe discussed individually in the study group. In case ofgrade 3/4 GI toxicities (including anorexia, dehydration,nausea/vomiting, diarrhoea, mucositis and bleeding)patients will be considered for periodic outpatient intrave-nous rehydration with anti-emetics according to conven-tional practice guidelines. Corticosteroids should beavoided. Any grade > 2 oto-, neuro-, or nephrotoxicityshould lead to discontinuation of cisplatin until recoveryto at least grade 1. All uncertain cases of toxicities will bediscussed by the study group and a decision will be madeaccording to the study group discretion. Patients will beinvestigated weekly for mental state. In case of psycholog-ical features, a psychiatrist will be consulted. Patients withmental diseases will be excluded.

Patients can withdraw from study participation at anytime. Patients are taken off the study if unacceptable tox-icity appears. Unacceptable toxicity is defined as seriousside effects or irreversible Grade 4 toxicity independentwhether they are expected or unexpected. Patients withmental diseases will be excluded as mentioned in exclu-sion criteria. Patients who withdraw from the study maybe treated with 5-FU and folinic acid or with gemcitabine.The decision will be based on the individual reason ofstudy withdrawal. Treatment with gemcitabine is recom-mended to patients with recurrence of disease. At themoment, no further therapy is recommended after com-pletion of adjuvant therapy. Patients will undergo imag-ing and lab analysis (including tumor marker) quarterlyand will be tracked by quarterly phone follow-up untildeath.

Statistical considerations and sample size estimationThe primary endpoint in this clinical trial is the event-freesurvival. An event is defined as time from resection toobjective tumour recurrence, grade 3 or grade 4 toxicity(according to CTCAE Version 3.0), or death (whicheveroccurs first). Secondary endpoints are as follows: a) OS,defined both as time from randomization and resection todeath; b) RFS, defined as either time from randomizationor as time from resection to relapse of death from anycause (whichever occurs first); c) QoL; d) Translationalresearch focussing on immunological and angiogenicparameters, and e) safety issues.

For each parameter, several (longitudinal) measurementswill be available. Apart from the parameter values them-

selves, further parameters will be generated, such as differ-ences, or relative differences, of values after vs. beforeadministration of INF-α2b or binary variables obtainedby applying threshold values. Sample size calculationswere based on the three-group comparison (differences inthe three 6-month event-free rates r1, r2, r3 correspondingto CapRI (Arm A), CapRI light (Arm B), and CapRI ultralight (Arm C), respectively and carried out by means ofcomputer simulations using the following main assump-tions: equal group sizes, failure times arising from anexponential distribution, individual follow-up durationof ≥ 6 months, duration of patient enrolment 6, 12, or 18months, For r1 = 2%, r2 = 10%, r3 = 15% the minimalsample size leading to an estimated power of ≥ 80% was37 per group. Similarly, for r1 = 2%, r2 = 5%, r3 = 15% thenecessary sample size estimated by the simulations was 38per group. From the experience gained during the CapRItrial it can be expected that about 15% of the patientsrefuse further participation in the trial (including furtherfollow-up examinations) once the result of the randomi-zation has been disclosed to them. These patients do notcontribute any information to the endpoints of this trial.In order to accommodate for a maximum drop-out rate of15% the total sample size is therefore increased to 135.The main evaluation will be performed two years after thelast patient's enrolment.

The assessment of safety will be based mainly on the fre-quency of AEs and on the number of laboratory valuesthat fall outside of pre-determined ranges and/or showprominent worsening from baseline. AEs will be summa-rized by presenting the number and percentage of patientshaving any AEs or serious adverse events (SAE) and havingeach individual AE, and by determining and summarizingthe maximum individual toxicity grade (over all forms oftoxicity) for each treatment cycle. Furthermore, the mostcommon AEs (those occurring in at least 10% of the treat-ment group) will be determined. Any other informationcollected (e.g. severity or relatedness to study drug) will belisted as appropriate. Laboratory data will be summarizedby presenting shift tables using normal ranges (baseline tomost extreme post-baseline value) and by presenting sum-mary statistics of raw data and change from baseline val-ues (means, medians, standard deviations, ranges). Theanalysis of safety and tolerability will be based on allpatients entered into treatment who received at least twocycles of the systemic study therapy (= per protocol popu-lation of this study). All proportions will be given alongwith exact Pearson-Clopper 95% confidence bounds.

DiscussionOnly 10–20% of patients with pancreatic cancer can beresected with curative intention at the time of diagnosis[19]. The 5-year survival of patients with resected pancre-atic adenocarcinoma is approximately 14% for patients



without adjuvant therapy [1]. Data from two randomizedclinical phase III trials showed that adjuvant chemother-apy results in significant increase of overall survival anddisease-free survival [2,3]. The Virginia Mason studygroup in Seattle, USA, published very promising data in aphase II trial involving immunotherapy and chemo-radi-ation in the adjuvant setting [5]. The reliability of the datahas been intensively discussed and therefore a source-data-verification was performed by the National CancerInstitute (NCI). Finally, the reference adjuvant treatmentregimen from a RCT [2] and the very promising data froma phase-II trial [5] were the basis for the randomized, con-trolled multicentre CapRI-trial [6]. First clinical results areexpected for 2009.

So far, the observed toxicity in the CapRI trial is less thanreported from the Virginia Mason Clinic and other groupsin USA. This might be due to differences in radiation treat-ment and supportive care during chemotherapy. How-ever, the CapRI-scheme is nonetheless a quite toxicregimen. In our experience haematological side effectsdominate, followed by gastrointestinal toxicity. Most ofthe toxicities are thought to be related to cisplatin. Fur-thermore, in vivo data indicate that the combination of 5-FU and INF-α2b is responsible for the anti-tumour effect[12,13,16,17]. Moreover, there are data supporting theidea that radiotherapy is of low effectiveness [2,20,21].Therefore, it is hypothesized that removal of cisplatin andradiotherapy will have no significant effect or only aminor impact on the clinical response but result in lowertoxicity. The current clinical trial, CapRI-2, will investigatethis hypothesis on the basis of a de-escalation of theCapRI-regimen. CapRI-2 is a phase II trial focussing onevent-free survival. Obviously, it has to be expected thattoxicity decreases when less chemotherapy is adminis-tered. However, as recurrence and death are defined asevents too, some insights into clinical relevance of the de-escalating schemes could be made. As a phase II trial thecomparison of OS can not be the primary objective of thistrial and moreover, a trial design showing equality or non-inferiority regarding survival and superiority regardingtoxicity would need thousands of patients. The results ofCapRI-2 will bring hints whether and which de-escalationmight be worth to be investigated in further trials. Theresults of the CapRI-2-trial will advance clinical and scien-tific knowledge on the adjuvant treatment of pancreaticadenocarcinoma as it may help to improve clinical resultson the one hand and reduce therapeutic-related toxicitieson the other.

Abbreviations5-FU: 5-Fluorouracil; AE: Adverse Events; CTCAE Version3.0: Common Toxicity Criteria 3.0; CRF: Case ReportForm; CRO: Contract Research Organisation; DFS: Dis-ease-free survival; DSMB: Data and Safety Monitoring

Board; GCP: Good Clinical Practice; GI: Gastrointestinal;NCI: National Cancer Institute; OS: Overall survival; QoL:Quality of Life; RCT: Randomized Controlled Trial; RFS:Recurrence-free survival; SAE: Serious Adverse Events

Competing interestsThe authors declare that they have no competing interests.

Authors' contributionsAM, MWB, MM, DJ, HF, JM and JS participated in thedesign of the study, UA was responsible for the statisticalplanning of the trial, JO and SH wrote the study protocol.All authors read and approved the final manuscript.

AcknowledgementsThe authors are grateful to Dr. HP Wild, the Leonie Wild Foundation, and the 'Capri-Sonne Company', all in Heidelberg for their generous grant.

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Pre-publication historyThe pre-publication history for this paper can be accessedhere:

http://www.biomedcentral.com/1471-2407/9/160/prepub


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AbstractBackgroundMethods/DesignDiscussionTrial Registration

BackgroundMethods/DesignTrial organisation and coordinationInvestigatorsData Safety and Monitoring BoardMedication supplyOn-site MonitoringEthics approval and informed consentPatient selectionStudy designStudy objectivesRandomisationTreatment schemeEvaluations, Toxicity-Based Dose Adjustment and follow- upStatistical considerations and sample size estimation

DiscussionAbbreviationsCompeting interestsAuthors' contributionsAcknowledgementsReferencesPre-publication history

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